Kinetic Resolutions - The Stoltz Group

N3
O
O
O
Epoxide Kinetic Resolution
While asymmetric epoxidation is much more practical for many compounds, some cannot be accessed in high ee
through current methods
In particular, terminal epoxides are difficult to get enantiopure, although the racemic epoxides are often
commercially available.
H2N
O
(±)-
Yamamoto
(±)-
O
15% recovered
27% ee
OTMS
R
R
1. CSA, MeOH
2. 10% Pd/C
MeOH, H 2
OH
R
(R,R)-18
TMSN 3
4.4 mol% 19
ArOH
TBME, 12-18 hr
-30 to 25 o C
O
Catalyst 17
CH 2Cl 2
-30 o C, 5 h
Ph
O
21% recovered
52% ee
R
ArO
PhO
R
OH
R
OH
O
O
O
20% epoxide recovered
>95% ee
TMSN 3
R
OTMS
+
O
O
(R)-(+)-17
Epoxide Kinetic Resolution - Jacobsen
+
(S,S)-18
R = alkyl, Bn, CH 2 Cl, c-C 6 H 11 , CH 2 OR,
CH(OEt) 2 , CH 2 CN, (CH 2 ) 2 CH=CH 2
2 mol% 18, 18-50 hr, 0 o C
Yields > 80% (based on 1 eq TMSN 3 )
ee > 90% (most > 97% ee)
s = 48 - 280
O
O
OBu
Al
Cl
Li +
Yamamoto, et. al., Tetrahedron, 1988, 44 (15), 4747
N 3
Wide range of Ar and R tolerated
Yields usually > 95%
(based on 1 eq ArOH)
Typically > 90% ee
Epibromohydrin (R = CH 2 Br) racemizes in presence of LiBr
Dynamic Kinetic Resolution was possible!
(±)-
Br
4 mol% 19
PhOH
4 mol% LiBr
CH 3 CN, MS3A
Br
74% yield
> 99% ee
N N
Cr
t-Bu O O
t-Bu
t-Bu
N 3
N N
Co
t-Bu
t-Bu O O
t-Bu
t-Bu
(R,R)-18
Jacobsen, et. al., J. Am. Chem. Soc., 1996, 118, 7420
(R,R)-19
t-Bu
- OC(CF3 ) 3 + H 2 O
Jacobsen, et. al., J. Am. Chem. Soc., 1999, 121, 6086
20